Processes and apparatus for extraction of active substances and enriched extracts from natural products

ABSTRACT

Processes for preparing extracts of natural products such as plant material, and for preparing purified extracts from crude extracts of natural products, by extraction with hot gas. Apparatus suitable for use in preparing extracts of natural products are also described.

RELATED APPLICATION

This application is a national stage filing under 35 U.S.C. § 371 of PCTInternational application PCT/GB02/02099, filed May 7, 2002, which waspublished under PCT Article 21(2) in English, which claims priority toGreat Britain patent application GB 0111046.9, filed May 4, 2001, theentire contents of which applications are incorporated by referenceherein.

FIELD OF THE INVENTION

The present invention relates to processes for preparing extracts ofnatural products, such as plant material, and for preparingpurified-extracts from crude extracts of natural products by extractionwith hot gas, and also to apparatus suitable for use in preparingextracts of natural products.

BACKAROUND TO THE INVENTION

The therapeutic activity of plant medicines is attributed to the activeconstituents which they contain. In some cases the intrinsic activity ofnatural products has been linked to specific chemical species, but inother cases the activity of the plant medicine is considered to be dueto a combination of constituents acting in concert. In most plantmaterials the active constituent is present in varying proportions. Forexample, vincristine is an alkaloid present in the aerial parts of Vincaroseaea at concentrations of less than 0.1% of the dried biomass. In thecase of cannabis resin, the concentration of active constituent may bemore than 60% w/w of resin (hashish). Whatever the concentration inbiomass, it is convenient to extract specific constituents, or producean enriched extract, which can be then formulated into conventionaldosage forms for ease of administration.

Methods of extraction which have been used to separate constituents ofplant medicines and to produce enriched extracts include maceration,decoction, and extraction with aqueous and non-aqueous solvents,distillation and sublimation.

Maceration (also known as simple maceration) is defined as theextraction of a drug in a solvent with daily shaking or stirring at roomtemperature. After a defined period the spent, solid material isseparated from the solution (macerate). Variation on the method includesagitation of the macerate and the use of temperatures up toapproximately 50° C. The method was formerly used for the preparation oftinctures and extracts from low-density plant materia medica, usingvarious strengths of ethanol as the extraction solvent.

Decoction has been used since antiquity for the preparation oftraditional medicines. In traditional Chinese medicine it is customaryto place the quantity of herbs required for one day's treatment into avessel to which hot or boiling water is added. The vessel is then raisedto boiling point and allowed to simmer for 1½ hours (sometimes longer).The decoction so produced is allowed to cool, separated from solidparticles, and the decoction is used as the dosage form for oraladministration.

Maceration and decoction rely on a short diffusion path. Inactiveconstituents such as lecithins, flavinoids, glycosides and sugars mayact to solubilise constituents which, in the pure state, are reallysoluble in the solvent. A disadvantage of maceration and decoction withwater or low concentrations of ethanol is that a large quantity of inertmaterial (ballast) that does not have therapeutic value is extracted.Ballast may consist of plant cell constituents including, but notlimited to, fats, waxes, carbohydrates, proteins and sugars. This maycontribute to microbiological spoilage if the product is not usedpromptly. If dried, the extracts so produced tend to be hygroscopic anddifficult to formulate. The ballast may also affect the way in which theactive constituents are absorbed from the finished dosage form.

Maceration and decoction are still widely used in situations where thebalance of convenience inherent in the low technology involved outweighsthe lack of precision in such technology in the context ofpharmaceutical production. In the case of macerates and percolates,solvents may be removed by evaporation at temperatures below 100° C. andpreferably below 60° C.

A wide range of processes based on the use of non-aqueous solvents toextract the constituents from plants have been used in the prior art.The solvents employed may be miscible with water or water immiscible andvary in solvent power according to the concept of E°, which is familiarin the context of chromatography.

Traditionally, ethyl alcohol in various concentrations has been used toextract active substances from plant materials. Tinctures are alcoholicsolutions produced in this way and tinctures of plant materials aredescribed in all major pharmacopoeias. Where the final concentration ofalcohol is greater than approximately 20% by volume, the tinctureremains microbiologically stable and such tinctures have been widelyused in compounding prescriptions. Ethanol extracts substances such asglycosides, flavinoids and alkaloid salts which are examples of classesof compound known to be biologically active. It also extractsconsiderable amounts of plant pigment, such as chlorophyll andcarotenoids. By using higher alcoholic strengths lipid-soluble materialmay be extracted. Tinctures contain less ballast than macerates ordecoctions, but are still complex mixtures of plant constituents. Wherethe presence of alcohol is not required the tincture can be evaporatedto produce extracts. All pharmacopoeias contain liquid and solidextracts produced in this way.

Lipid solvents with a high E° value have been used to extract lipidsoluble constituents from biomass. Examples are chlorinated solventssuch as dichloromethane, chloroform and carbontetrachloride, hexane,ether, fluorinated hydrocarbons and supercritical fluid extraction withagents such as carbon dioxide.

Chlorinated solvents are no longer used commercially for extraction ofplant biomass because they are themselves toxic and for pharmaceuticaluse the solvent must be removed. They are, however, reactive and canalso result in the production of compounds which have been shown to begenotoxic—and may even be carcinogenic. Hexane and other petroleum-basedsolvents have a high E° value and good solvent activity, but they mustbe completely removed from the end product and also carry with them riskof fire and explosion.

Extraction with supercritical fluid CO₂ has been used to remove activeconstituents from foods such as caffeine from coffee beans, and humuleneand other flavours from hops (Humulus lupulus). The process allows formanipulation of E° value by variation of pressure, temperature and bythe addition of accessory solvents (modifiers) such as alcohols.

A characteristic of all non-aqueous solvent methods of extraction isthat they all, to a greater or lesser degree, remove lipid solubleinactive material or ballast from plant material. The ballast mayconsist of plant cell constituents including but not limited to fats,waxes, carbohydrates, proteins and sugars. The presence of thesesubstances results in botanical extracts which may be hygroscopic,difficult to reduce to a powder and generally intractable as startingmaterials for pharmaceutical preparations. The presence of ballast mayalso limit the shelf-life of pharmaceutical products formulated fromsuch extracts.

Some elements of ballast can be removed by an additional steppost-extraction referred to as “winterisation”, which involves making aconcentrated solution of the extract and cooling it to a temperature atwhich a proportion of waxes and lipid components may be precipitated,typically −20° C.

Partially purified plant extracts may be further purified bychromatographic separation. High performance liquid chromatography(HPLC) is an excellent analytical technique for determination and assayof constituents and can be used in preparative mode to produce pilotquantities of concentrated fractions and individual components, providedthat the required reference standards are available. However, HPLC issubject to limitations of scale as a production technique and thereremains a need for alternative methods of separation which can be usedto produce production-scale quantities of plant extracts of sufficientquality for formulation into pharmaceutical dosage forms.

Distillation and sublimation have been used to separate components ofplant medicines which have boiling points at or around the temperatureat which water boils at atmospheric pressure (100° C.). Separation bydistillation is a physical process widely used in the preparation ofessential oils.

GB 635,121 describes a process for the preparation of extracts fromaromatic plants by distillation with the help of a hot gas, preferablyunder high vacuum.

WO 99/11311 describes a vaporizer for inhalation and a method for theextraction of active ingredients from a crude natural product. Thismethod utilizes an ascending stream of hot air, or a heated inert gasstream, to volatilize components from the natural product. The resultantvapour may then be inhaled by a user, for example to provide therapeuticbenefit.

The present inventors have now determined that useful separation ofcertain plant constituents, which are not considered to be volatile atambient temperatures, can be effected by extraction with a gas heated tohigher temperatures than those traditionally used in distillation.Accordingly, they have developed a process for the preparation ofextracts from natural products which avoids many of the disadvantages ofthe prior art and provides additional technical advantages, particularlyin the extraction of pharmacologically active components from plantmaterial.

SUMMARY OF THE INVENTION

In accordance with a first aspect of the invention there is provided aprocess for preparing an extract from a natural product which comprisescontacting the natural product with a heated gas at a temperature whichis greater than 100° C. and sufficient to volatilise one or moreconstituents of the natural product but does not cause pyrolysis of thenatural product thereby volatising one or more constituents of thenatural product to form a vapour, and condensing the vapour to form anextract.

In accordance with a second aspect of the invention there is provided aprocess for preparing an extract from a natural product which comprises:

-   -   providing a primary solvent extract of the natural product;    -   contacting the primary solvent extract with a heated gas thereby        volatilising one or more constituents of the primary solvent        extract to form a vapour;    -   condensing the vapour; and    -   collecting the condensate in one or more fractions.

According to a further aspect of the invention there is provided anapparatus for extracting useful substances from natural products, theapparatus comprising a receptacle for receiving the natural product, ablower to blow gas through the receptacle, a heater for heating the gasblown through the receptacle, a condenser to condense the vapour fromthe receptacle, and a means for collecting the useful substances in thecondensed liquid.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be further understood with reference to the drawings,in which:

FIG. 1 is a schematic diagram of a first apparatus in accordance withthe present invention;

FIG. 2 is a cross-section through the rotatable drum of FIG. 1;

FIG. 3 is a section through the drum in a plane perpendicular to theaxis of rotation;

FIG. 4 is a schematic diagram of a second apparatus; and

FIG. 4A shows the detail of a basket used in FIG. 4.

FIG. 5 is a schematic diagram of an apparatus suitable for carrying outthe solvent extract purification process of the invention.

FIGS. 6-10 are gas chromatogram traces showing the c position offractions volatilized and condensed from cannabis botanical raw materialat various temperatures, in comparison with the starting raw materialand spent herb.

DETAILED DESCRIPTION OF THE INVENTION

The process according to the first aspect of the invention combines adistillation step in which the natural product is contacted with a hotgas, resulting in volatilisation of one or more constituents of theproduct to form a vapour, with a condensation step in which the vapouris condensed to form an extract.

If required, the process may further include a step of removingparticulate matter from the vapour prior to the condensation step.

The process exhibits unexpected efficiency and selectivity as comparedto prior art methods of solvent extraction, particularly in relation tothe isolation of cannabinoid-rich fractions from cannabis plant material(as illustrated in the accompanying examples).

Contact between the natural product and the heated gas is advantageouslyachieved by “gas washing” the product. This involves continuousagitation of the product in a stream of the heated gas.

The process may be operated continuously and as such is particularlysuitable for use in large scale commercial production of extracts fromnatural products.

As illustrated in the accompanying Examples, the process of theinvention can produce extracts containing minimal ballast which aresuitable for direct formulation into standard pharmaceutical dosageforms, i.e. tablets, capsules, sprays, liquid formulations etc.

The condensed extract may be a homogeneous liquid but may, depending onthe nature of the starting material, form a mixture of oily and aqueouscomponents. In the latter case, the apparatus used for carrying out theprocess may include further means for separating the extract intofractions by passing vapour into a condenser with a fractionatingcolumn. This type of condenser is commercially available and containsbaffle plates or other packing and multiple collection ports forseparation of fractions having different boiling points.

The extraction process of the invention is particularly preferred forpreparing extracts from plant material. The term “plant material”encompasses whole plants and also parts thereof which contain theprincipal medically active constituents, for example the aerial parts ofthe plant or isolated leaves, stems, flowering heads, fruits or roots.The extraction process may be carried out starting from freshlyharvested plant material, plant material which has previously been driedby removal of water or plant material which has been subjected to someother pre-treatment step, for example to effect a chemical change inconstituents of the plant material.

When using freshly harvested plant material, for example plant materialwhich is still green, the process may advantageously include apre-treatment step in which the plant material is contacted with astream of heated gas at a temperature which is sufficient to dry theplant material, by removal of water vapour therefrom. After this initialpre-treatment step the temperature of the heated gas may be increased toa temperature which permits volatilisation of constituents of the plantmaterial.

The precise temperature of the gas used to volatilise constituents ofthe natural product may vary dependent on the nature of the naturalproduct and on the nature of the constituents it is desired to extractusing the process. However, the temperature is always be above 100° C.(during at least a part of the extraction process) and is selected notto cause substantial pyrolysis of the natural product. Typicaltemperatures will be in the range of from 150 to 450° C. The extractionis preferably carried out at or above atmospheric pressure.

The temperature may be varied over the course of the extraction process.In one embodiment a profile of two or more discrete temperatures may beused, at least one of which is above 100° C. and selected not to causesubstantial pyrolysis of the natural product. Most preferably thetemperature of the heated gas will be increased at each of the discretesteps. In a further embodiment the temperature of the heated gas couldbe continuously increased or ramped. The use of heated gas at two ormore discrete temperatures may enable components of the natural productsto be volatilised and condensed as separate fractions.

Suitable “heated gases” for use in the process include hot air. However,the use of hot air can result in oxidative degradation of constituentsof the extract produced during the extraction process. This problem canbe avoided with the use of a “non-oxidising gas”. By the term“non-oxidising gas” is meant a gas which causes less oxidation of theextract produced from the natural product than air under equivalentprocess conditions. A preferred type of “non-oxidising” gas is dry steami.e. steam at a temperature above 100° C. which is free of condensedwater vapour.

Further protection against the effects of oxidation can be achieved withthe use of a “reducing gas”. Suitable reducing gases include gasescontaining a pharmaceutically acceptable anti-oxidant, sulphur dioxidemixed with steam, carbon dioxide and inert gases such as, for example,nitrogen, helium and argon. The use of a reducing gas is particularlyadvantageous in relation to the extraction of cannabinoid-rich fractionsfrom cannabis plant material, as discussed below.

In one particular embodiment, useful for preparation of extracts fromfreshly harvested or “wet” plant material, a reducing gas may beproduced in situ by addition of a solution of sodium metabisulphite to astream of heated steam. When mixed with wet plant material, sodiummetabisulphite reacts to produce sulphur dioxide which provides anantioxidant environment, minimising the extent of oxidation of theextract. The quantity of sodium metabisulphite added to the steam istypically sufficient to give 10-500 parts of sulphur dioxide per millionparts of wet plant material.

Surprisingly, it has been found that application of temperatures greaterthan those used for steam distillation can also speed the conversion ofinactive constituents of natural products into compounds which arebiologically active and can be separated in high purity by heating andcondensation under defined conditions. For example, the principal activeconstituents of Cannabis saliva and Cannabis indica are thecannabinoids—principally tetrahydrocannabinol (THC) and cannabidiol(CBD). Cannabinoids such as cannabigerol (CBG), cannabichromene (CHC)and other cannabinoids are present in small quantities in harvestedcannabis plants. The majority of cannabinoids are present in the plantas the corresponding carboxylic acids. The carboxylic acids themselveshave little or no biological activity and in the production ofcannabinoids for medicinal use it is necessary to convert thecannabinoid acids into free cannabinoids before extracting with solventsor other procedures. Thus when preparing extracts of cannabis byextraction with ethanol or supercritical CO₂ it is necessary to preheatthe cannabis in order to decarboxylate the cannabinoid acids to freecannabinoids.

Surprisingly, it has been found that by contacting cannabis biomass withgas at a temperature of 105-450° C., and particularly in the range105-225° C., for a suitable period of time, the carboxylic acids areconverted into free cannabinoids which are vaporised, and can becondensed. The process of the invention can therefore avoid the need fora separate decarboxylation step, since extraction of cannabis withheated gas at a temperature of 105-450° C., and preferably in the range105-225° C., results in decarboxylation and vaporisation of the activecannabinoids in a single step. The process of the invention isparticularly advantageous for preparing extracts of cannabis for thisreason. The rate of decarboxylation is a product of temperature andtime. At 145° C. 95% of cannabinoid acid is decarboxylated inapproximately 30 minutes. Lower temperatures may require a longerincubation time and higher temperatures a shorter incubation time toachieve the same degree of decarboxylation. Again this process ispreferably carried out at or above atmospheric pressure.

Preferred temperatures and times to achieve optimum decarboxylation mayvary according to nature of the cannabinoids which it is desired toextract from the cannabis plant material. Chemovars of cannabis havebeen produced which express a high proportion (typically >80% and morepreferably >90%) of their total cannabinoid content as either THC orCBD. For convenience, these chemovars are referred to as the “high THC”and “high CBD” chemovars, respectively. In the case of “high CBD”plants, preferred time/temperature profiles to achieve completedecarboxylation are 120° C. for 1 hour or 140° C. for 30 mins. For “highTHC” plants it is preferred to use a lower temperature in order to avoidthermal oxidation of Δ⁹-THC to CBN and thermal isomerisation of Δ⁹-THCto Δ⁸-THC. Therefore preferred time/temperature profiles are 105° C. for1-2 hours or 120° C. for 30-60 mins. For both high CBD and high THCchemovars higher temperatures may be used in order to prepare extractswhich are substantially free of volatile ballast components, for exampleterpenes, as discussed below.

A further surprising advantage of the process of the invention inrelation to the isolation of cannabinoid-rich fractions from cannabisplants is that the condensate so produced contains the free cannabinoidsin a high degree of purity, substantially free from waxes, sterols andother lipid-soluble components which characterise solvent extracts.Table 1 shows the percentage purity of the extract which is producedwith the equipment described in the attached diagrams, according to theprocess described in the accompanying examples. For comparison purposesTable 1 also shows the content of free cannabinoid and the correspondingcarboxylic acids in extracts produced by alcoholic extraction andextraction with supercritical carbon dioxide. The table also shows thepercentage of ballast which is extracted by these methods. It can beseen that the extraction process of the invention results in an extractwhich is substantially free of ballast. This extract is of sufficientquality to be processed directly into pharmaceutical dosage forms. Incontrast, cannabis extracts prepared by extraction with ethanol orsupercritical CO₂ contain a large proportion of ballast. For example,whilst CO₂ extraction is relatively selective, typically yielding anextract with a cannabinoid content of approximately 70% w/w, a range ofnon-cannabinoid ballast is also present. The process of the inventionexhibits markedly increased selectivity for extraction of cannabinoids.

Most of the ballast present in cannabis plant material is involatilematerial. The process of the invention is efficient in separating thedesired active cannabinoids from this involatile ballast, since the vastmajority of this involatile ballast is simply not volatilized during thehot gas extraction procedure. Thus, removal of waxy ballast material maybe unnecessary, or at least rendered easier than with a solvent extract.The other major ballast component is a volatile terpene-rich fraction.An unknown component of this terpene-rich fraction is suspected to bethe cause of stability problems in solvent extracts of cannabis plantmaterial prepared using supercritical CO₂ extraction. Hence, it ishighly desirable to remove the volatile terpene-rich fraction.

Using the process of the invention it is possible to collect acannabinoid-rich fraction which is substantially free of volatileterpenes and wherein the majority of the cannabinoids are present in thedecarboxylated neutral form using a single-step temperature profile.This has obvious advantages in comparison to, for example, extractionwith CO₂ or ethanol in that there is no need for a separatedecarboxylation step prior to extraction or for a separate“winterisation” step to remove ballast. Furthermore, the extract issubstantially free of volatile terpenes which may cause stabilityproblems. As illustrated in the accompanying examples, for “high CBD”material a single temperature step in the range of 175-200° C. mayresult in the isolation of a cannabinoid-rich fraction which issubstantially free of terpenes. At these temperatures terpenes arevolatilised along with the cannabinoid-rich fraction but are notcondensed, and are thus lost from the system. In the case of “high THC”material it is preferred to use a lower temperature in order to avoidthermal oxidation of Δ⁹-THC to CBN or thermal isomerisation of Δ⁹-THC toΔ⁸-THC. Temperatures in the range 130-175° C. are preferred. The skilledreader will, however, appreciate that the optimum temperature may varydepending on the characteristics of the apparatus used to carry out theprocess, for example the amount of raw material processed in eachcharge, time of contact with the extracting gas and also the conditionsused for condensation of the volatilised components. Thus, for any givensystem conditions of extraction temperature and time should be optimisedempirically.

The terpene-rich fraction isolated from cannabis raw material may itselfhave a commercial value as a “waste” product. Hence, it may beadvantageous to split the volatile components into terpene-rich andcannabinoid-rich fractions which are condensed and collected separately.This may be achieved by use of a multi-step temperature profile, usingat least two discrete temperatures. Since the terpene-rich fraction ismore volatile than the cannabinoid-rich fraction it can be removed in aninitial extraction step at a lower temperature. The temperature may thenbe increased in order to volatilise the cannabinoid-rich fraction. Thetemperature required to preferentially volatilise terpenes may varydepending on the nature of the starting cannabis plant material, but canbe readily determined by experiment as would be apparent to one skilledin the art. By way of example, for “high CBD” material a temperature inthe range 125-150° C. is observed to result in preferentialvolatilization of a terpene-rich fraction. Whereas, for “high THC”material a temperature in the range 60-90° C. is required. In order tooptimise condensation of the volatile terpene fraction the conditionsused for condensation may also be varied, in addition to the temperatureof the heated gas used to volatilize this component.

Once the terpene-rich fraction has been removed, the temperature of thehot gas may be increased in order to volatilise the cannabinoid-richfraction. Again, the optimum temperature for extraction of the desiredcannabinoid components may be determined by experiment. By way ofexample, for “high CBD” cannabis plants a temperature in the range175-200° C. is preferred. Whereas, for “high THC” cannabis plants atemperature in the range 130-175° C. may be suitable. At 200° C. acannabinoid-rich fraction may still be collected but thermal degradationof Δ⁹-THC is increased. Hence it is preferred to use a lowertemperature.

Thus, the skilled reader will appreciate that by simple empiricalvariation of the conditions used for volatilisation and condensation itis possible to optimise separation of the terpene-rich andcannabinoid-rich fractions.

A still further advantage of the process of the invention in relation tothe preparation of cannabinoid-rich fractions from cannabis plants isthat the extracts prepared using the process contain cannabinoidcomponents in approximately the same ratio as present in the startingmaterial. Thus, substantially no fractionation of the cannabinoids isobserved.

In the context of this application the terms “cannabis”, “cannabis plantmaterial” or “cannabis biomass” refer to whole cannabis plants and alsoparts thereof which contain the principal medically active constituents,for example the aerial parts of the plant or isolated leaves and/orflowering heads. The terms “cannabis” and “cannabis biomass” encompassfreshly harvested plant material, and also plant material which has beensubjected to a pre-treatment step such as, for example, material whichhas been dried. This includes cannabis material which has been allowedto air dry after harvesting.

It is convenient to process high CBD and high THC cannabis chemovarsseparately to produce extracts rich in either THC or CBD from whichmixtures containing defined proportions of THC and CBD can be made inthe preparation of pharmaceutical formulations. Procedures described inthe following examples with reference to one particular chemovar may beapplied mutatis mutandis for any other cannabis chemovar.

In a further embodiment of the invention the principle of extractionwith a heated gas may be utilised in a two-stage process for thepreparation of extracts from plant materials which involves firstpreparing a primary solvent extract from the plant material.

As discussed previously, it is known to make an extract from plantmaterial by percolation or maceration with a solvent and to fractionatethe extract by concentration or various processes which have beendescribed in the scientific literature for reducing extracts to apowder. However, botanical extracts prepared using such processesgenerally contain a variable, but usually considerable, proportion ofinactive material or ballast which renders the extracts generallyintractable as starting materials for pharmaceutical preparations.

The inventors have now observed that primary solvent extracts of naturalproducts, such as plant material, may be further purified by extractionwith a heated gas, resulting in removal of a substantial proportion ofthe inactive ballast.

Therefore, in accordance with a second aspect of the invention there isprovided a process for preparing an extract from a natural product whichcomprises:

-   -   providing a primary solvent extract of the natural product;    -   contacting the primary solvent extract with a heated gas thereby        volatilising one or more constituents of the primary solvent        extract to form a vapour;    -   condensing the vapour; and    -   collecting the condensate in one or more fractions.

This process (referred to hereinafter as the “solvent extractpurification” process) may be used to prepare a “purified” extractstarting from a primary extract of a plant material. The term “purifiedextract” refers to an extract which retains one or more desirableconstituents from the starting primary extract but contains a loweramount of other, undesirable constituents. In a preferred embodiment thesolvent extract purification process may be used to prepare a purifiedextract which retains pharmacologically active constituents from theprimary extract whilst removing unwanted ballast.

The primary extract used as the starting material for the solventextract purification process may be essentially any solvent extract of aplant material such as, for example, cannabis plant material. Extractsprepared with alcohols such as, for example, ethanol, methanol,isopropanol or industrial methylated spirit are particular suitable.Another suitable solvent is acetone. Extracts prepared by extractionwith supercritical CO₂ may also be used.

Solvent extracts prepared with alcohols may be dried down by evaporationof the solvent to yield a soft extract (as defined in the BritishPharmacopoeia) and then re-dissolved in the same or a different solventprior to contact with the heated gas. This will allow for adjustment ofthe concentration and viscosity of the extract prior to contact with theheated gas. The term “primary solvent extract” as used herein istherefore to be construed as encompassing extracts which have been drieddown and re-dissolved.

In the case of cannabis, it is preferred to use a primary extractprepared using a mixture of alcohol and water. The use of such mixturesreduces the lipophilicity of the solvent system and leads toproportionately greater extraction of cannabinoid acids. The extractionof cannabinoid acids in progressively more dilute alcohols is observedto be increased at high pH.

The primary solvent extract may be prepared using conventionaltechniques known in the art such as, for example, maceration,percolation and reflux (Soxhlet) extraction. The solvent used forprimary extraction may be chosen according to the known solubilitycharacteristics of the active ingredients or their precursors in theplant material. Since it will be subject to a further extraction stepthe primary solvent extract may be a fairly crude extract.

In a preferred embodiment the step of contacting the contacting theprimary solvent extract with a heated gas comprises loading the primarysolvent extract onto a matrix of inert, porous material and circulatinga heated gas through the matrix, thereby volatilising one or moreconstituents of the primary solvent extract to form a vapour.

The primary solvent extract is loaded onto a matrix of inert, porousmaterial which provides a large surface area for contact between theprimary extract and the heated gas. Suitable inert matrix materialsinclude glass wool, which may be coated (e.g. silanised) to modify itssurface retentiveness. In one embodiment the glass wool may be in theform of a pre-formed mat of spun glass (Rockwool), rolled to form acylinder. Other suitable inert, porous matrix materials include, forexample, glass beads or short sections of glass tube, borosilicate glassor pharmaceutical grade stainless steel. For convenience, the matrixmaterial maybe packed into a column formed of an inert material, such asborosilicate glass. A suitable apparatus is described below andillustrated in the accompanying examples.

Heated gas is then circulated through the matrix material in order tovolatilise one or more constituents of the primary solvent extract,forming a vapour. The temperature of the heated gas will vary dependingon the nature of the component(s) which it is desired to volatilise fromthe primary extract. The temperature of the heated gas may also bevaried over time. For example, depending on the composition of theprimary extract it may be desirable to circulate heated gas at a firsttemperature in order to volatilise unwanted components of the primaryextract and then to adjust the temperature to a second, highertemperature to volatilise desirable components of the primary extract.

Suitable “heated gases” for use in the process include hot air, inertgas and dry steam, alone or in combination. The most preferred gases areinert gases, dry steam and mixtures thereof. Mixtures of inert gas anddry steam are referred to as anaerobic gas mixtures. By excluding air,through use of an anaerobic gas mixture, oxidative degradation of theextract is reduced or avoided. Examples of suitable anaerobic gasmixtures are dry steam mixed with one or more of nitrogen, carbondioxide, helium or argon.

Oxidation can be further reduced by use of a reducing gas mixture. By“reducing gas mixture” is meant an anaerobic gas mixture containing aproportion of a volatile antioxidant, or means for generating anantioxidant in situ during the extraction process.

The vapour produced by volatilisation of constituents of the primarysolvent extract is condensed and collected. The condensate may be ahomogeneous liquid but may, depending on the nature of the startingmaterial, form a mixture of oily and aqueous components. In the lattercase, the apparatus used for carrying out the process may furtherinclude means for collecting the condensate in two or more separatefractions.

The primary solvent extract may be subjected to a chemical treatmentprior to loading onto the inert matrix. In one embodiment, the extractmay be treated to adjust pH, for example by addition of an acid or analkali. Where the active constituent which it is desired to isolate fromthe plant material is an alkaloid salt or other adduct, the alkaloid maybe rendered volatile by adjustment of pH. Subsequent treatment withheated gas at a temperature which volatilises the alkaloid may thenresult in a product which is substantially free of inactive ballast.

Surprisingly, it has been found that use of the solvent extractpurification process can speed the conversion of inactive constituentsof plant materials into compounds which are biologically active and canbe separated in high purity. For example, as described above thecannabinoids which are the principal active constituents of cannabisplants, particularly Cannabis saliva and Cannabis indica, are present inthe plant as the corresponding carboxylic acids. With use of the solventextract purification process it is possible to prepare a purifiedcannabis extract, containing a high proportion of free cannabinoids,starting from a primary solvent extract. There is no need to perform aseparate decarboxylation step before preparation of the primary solventextract. A primary extract is simply prepared from cannabis plantmaterial, loaded onto matrix material and treated with heated gas.Circulation of the heated gas through the primary solvent extractresults in decarboxylation of cannabinoid acids and volatilisation offree cannabinoids in a single process step. The vapour comprising thefree cannabinoids is collected by condensation. The resulting condensateis substantially free of inactive ballast and suitable for formulationinto pharmaceutical dosage forms.

The temperature of the heated gas used in the processing of cannabisextract must be sufficient both to effect decarboxylation of cannabinoidacids and to volatilise the free cannabinoids. Temperatures in the rangeof 105°-350° C., and preferably 125°-218° C. are suitable for thispurpose. Decarboxylation of cannabinoid acids is a function of time andtemperature, thus at lower temperatures a longer period of time will betaken for complete decarboxylation of a given amount of cannabinoidacid.

According to a further aspect of the invention there is provided anapparatus for extracting useful substances from natural products, theapparatus comprising a receptacle for receiving the natural product, ablower to blow gas through the receptacle, a heater for heating the gasblown through the receptacle, a condenser to condense the vapour fromthe receptacle, and a means for collecting the useful substances in thecondensed liquid.

In one embodiment, the receptacle is a drum rotatably mounted in ahousing to rotate about an axis. Alternatively, the receptacle comprisesa stack of baskets each having a perforated base which allow the passageof gas, but substantially not the natural product.

Examples of apparatus according to the invention will now be describedwith reference to FIGS. 1 to 4.

The primary component of the apparatus shown in FIGS. 1 to 3 is arotatable drum 1 which is mounted in a housing 2. The drum 1 is mountedfor rotation about an axis 3. The drum 1 has an octagonal cross-sectionin a plane perpendicular to the axis 3 as shown in FIG. 3. Each side ofthe drum 1 comprises a mesh sheet 4 having a wire diameter of 0.16 to0.28 mm and an open area of 45 to 39% which is designed to retainparticles of 1×2 mm. The front of the drum is closed by a plate 4Abolted in place and held by a plurality of wing nuts 4B.

The drum 1 is driven by a variable speed geared motor 5 coupled viatorque coupling 6 to a rotatable shaft 7 supported on a pair of bearings8. The rotatable shaft 7 enters the housing 2 through a lip seal 9 andhas a key groove 10 which engages with a complementary key rib in thedrum so as to transmit rotational movement thereto. A drain part 2A isprovided in the bottom of the housing 2 to allow any accumulated liquidin the housing to be drained.

The housing 2 is open at the end opposite to the motor 5. This openingis selectively closable by a hinged door 11 and seals by virtue of anannular seal 12. The door 11 is provided with an inspection window 13 asshown in FIG. 1. The loading and unloading of the product isaccomplished by removing the wing nuts 4B and hence plate 4A, removingany spent product, replacing it with fresh product and replacing theplate 4A and wing nuts 4B. To clear the equipment between batches, theentire drum 4 may be removed from the housing 2, by unfastening the drumfrom the shaft 7. The drum 4 can then be cleaned and reused. It will bequicker, however, to have a second drum which is pre-filled with productand can be used in place of the first drum while the first drum iscleaned.

Hot gas is blown into the housing 2 through an air knife 14 suppliedfrom hot gas supply nozzle 15. The air knife 14 provides a long thin airduct extending parallel to axis 3 for substantially the entire length ofthe drum 1. The air knife 14 is positioned immediately adjacent to thedrum 1, and is directed generally towards the centre of the drum, butnot directly at the axis 13.

In use, a natural product such as medicinal cannabis is coarsely choppedand loaded into the drum 1 as described above. The cannabis may be inits “as grown” state, or may have been subjected to a pre-treatmentstep, for example a drying step. Typically 5 kg of cannabis will beloaded into the drum. A gas such as nitrogen is injected through a duct20 and is blown by a sealed fan 21 through a heater 22, where it isheated to a temperature of around 200° C., via hot gas supply duct 15and into the housing 2 through the air knife 14. Simultaneously with thegas injection, the drum 1 is rotated by the motor 5 at a rate of between0.1 and 60 r.p.m. This rotary motion causes the product to fall throughthe space in the drum, while the hot gas flowing through the air knife14 keeps the product away from the walls of the drum. The hot gas causesthe active substances within the product to vaporise and the hot vapourleaves the housing 2 through an outlet 16. A filter 17 traps largeparticles entrained in the vapour.

The vapour then travels along discharge duct 23 to a cyclone separator24 which separates out smaller particles from the vapour. It is possiblethat either the filter 17 or the cyclone separator 24 will be sufficienton its own to separate out all of the particulates from the vapour.

The vapour which is now substantially free of solids leaves the cycloneseparator 24 through cyclone outlet duct 25 and passes through the fan21. Temperature can be equilibrated and vapour can be recirculated byclosure of motorised butterfly valves 26 and 26A. Vapour passes througha condenser 28. The condenser 28 is cooled by a water jacket 29 to whichwater is supplied through duct 30 and returned through duct 31. Thedistillate leaving the condenser 28 containing the active substanceaccumulates in collector 32. The vapour may be vented via a steam trap33 or may be recirculated via a scrubber 34 or an iced chiller 35 alongreturn line 36 where it joins the recirculating hot gas stream upstreamof the heater 22. The scrubber 34 may be a glass wool or charcoalscrubber and is designed to remove the smell from the vapour. Apreferred type of scrubber contains C18 reverse-phase chromatographysupport in granular, permeable form which effectively absorbs anyparticles of lipid-soluble material. The chiller 35 is provided to chillthe vapour to condense terpenes. A typical design of chiller utilises afreezing mixture of acetone and solid carbon dioxide giving atemperature of −65-70° C. to condense remaining traces of vapour.

Prior to use, and before any natural product is placed in the drum, theapparatus is flushed with nitrogen which is then vented through vent 36prior to heating.

A dry steam inlet 38 may also be provided to give an anaerobicalternative to nitrogen. Dry steam allows vaporisation to occur at alower temperature than with nitrogen.

In practice, the apparatus upstream of the condenser (i.e. the housing1, heater 22 and cyclone 23) will be housed in a common insulatedcontainer to avoid expensive lagging of individual components.

An alternative apparatus is shown in FIG. 4. As with the example in FIG.1, the apparatus in FIG. 4 is also designed to force a stream of heatedgas through a perforated container holding a supply of natural productssuch as medicinal cannabis.

The apparatus of FIG. 4 comprises a sealed and insulated housing 40 intowhich gas flows through a heated gas inlet 41. This inlet 41 passesthrough a heat exchanger 42 such that the cold incoming gas is heatedwith hot outgoing gas as will be described below. The interior of thehousing 4 is heated by an electric heater 43 such that the preheated gasentering the housing 40 is heated further. A fan (not shown) is providedto drive the air into the housing 40. A double acting pump 44 ispositioned within the housing 40. This consists of a piston 45 whichreciprocates within a cylinder 46. The pump has a first inlet valve 47which allows air into the top of the cylinder during the pistondownstroke and a second inlet 48 which allows air into the bottom of thecylinder during the piston upstroke. A first outlet 49 lets air out ofthe top of the cylinder during the piston upstroke while a second outlet50 allows air out of the cylinder during piston downstroke. Flow througheach of the inlet and outlet valves is controlled by a one-way flapvalve. Thus, the double acting pump 44 provides a cyclic varying outputof hot gas which is conveyed via a duct to a carousel assembly 51.

The carousel assembly 51 comprises an upper disk 52 and an axiallyaligned lower disk 53, both of which are connected to a spindle 54 whichpasses through their centres. The spindle is rotatable so as to rotatethe upper 52 and lower 53 disks. Each of the upper 52 and lower 53 diskspasses through the wall of the housing 40 and a seal 55 is provided ateach interface. Each disk 52, 53 is provided with a number, preferablytwo or more and typically six, of circular orifices 56, each of which issized to receive a basket 57. Baskets 57 have a mesh base 57A and solidwalls 57B with a recess in the rim to retain a silicone rubber ringwasher 65. The baskets nest together and the ring washer ensures thatgas passes through the baskets and their content and not around them.The baskets 57 are loaded by upper disk 52 into a column 58. The firstloaded basket drops down the column 58 and is supported above a seriesof baffles 59 at the lower end of the column 58. Further baskets 57 arethen loaded on top of this.

Initially, a full stack of baskets is inserted as shown. The doubleacting pump 44 is then operated to push hot gas upwardly through thecolumn. Gas expelled from the top of the column passes through heatexchangers to pre-heat the incoming gas. The flow of hot gas up column58 vaporises the active ingredient as in the previous example, and theexpelled vapour is treated as previously described with reference toFIG. 1, namely be being passed through a separator such as a filter orcyclonic separator into a condenser 60. Also shown in this example is anoptional secondary condenser 61 and exhaust pump 62. The condenser 60has an upper outlet 63 and lower outlet 64 to allow withdrawal ofdifferent fractions of the condensate should it separate into layers.Such an arrangement may also be employed with the condenser of FIG. 1.

As the process progresses, the product in the lowermost basket 57 willbe exhausted at a faster rate than the product in successively higherbaskets because it encounters the freshest gas, i.e. a counter currentflow arrangement is operated. After a certain time, or once the level ofactive substances being collected has dropped below a certain level, thelowermost basket is removed by rotation of the lower disk 53 which takesthe basket outside the housing 40 where it can be removed for disposal.A fresh basket is pre-loaded into an orifice 56 in the uppermost basket52 outside the housing 40. As the lowermost basket is removed, the upperdisk is rotated bringing the fresh basket into a location at the top ofthe column 58. A reciprocable plunger 66 is then deployed to push thenew basket out of the hole 56 in the upper disk 52 and to ensure thatall of the baskets 57 are pushed down the column 58 so that thelowermost basket rests on the baffles 59.

After a suitable interval, this process is repeated so that freshbaskets of product are periodically added to the top of the column andgradually progress down the column until they are removed from thebottom.

FIG. 5. shows a small scale laboratory apparatus suitable for carryingout the solvent extract purification extraction process. This apparatusmay be assembled from commercially available proprietary laboratoryglassware. The apparatus comprises a hollow cylindrical column 69 formedof borosilicate glass or similar inert material. The column is packedwith an inert matrix material 70, for example glass wool, glass beads orshort sections of glass tube. A heating mantle 71 is fitted aroundcylindrical column 69 and provides heat and insulation to maintain thecylinder at its operating temperature. In other embodiments the columnmay be contained within an oven which is maintained at a specifictemperature controlled by a thermostat.

The apparatus further includes a re-circulation pipe 72 fitted with avalve 73 and sampling port 74 and a outlet pipe 75 also fitted with avalve 76 which feeds into the condenser assembly. The condenser assemblyof the apparatus shown in FIG. 5. includes two condensers 77,78 arrangedin series.

Heated gas is introduced into the device via an inlet port 79 at thebottom of the cylindrical column. A stream of heated gas may beconveniently provided using an electrical heater/blower device.

The re-circulation pipe 72 operates to re-circulate gases though thecolumn when valve 73 is in the open position and valve 76 is in theclosed position. When valve 73 is closed and valve 76 is open gases exitthe cylinder via outlet pipe 75 and are delivered to the condenserassembly. Condensate exiting the condenser assembly is collected in areceiving vessel (not shown).

The apparatus further includes a thermistor 80 and flow gauge 81 formonitoring the temperature and flow of gas in the apparatus.

The invention will be further understood with reference to thefollowing, non-limiting, experimental examples.

EXAMPLE 1 Extraction with Ethanol

The following method of extraction is essentially that described inmajor pharmacopoeias such as the British Pharmacopoeia, EuropeanPharmacopoeia and United States Pharmacopoeia. It is included here toprovide a datum point for comparison of the extracts produced by methodsillustrated in later examples. The method can be used mutatis mutandisto prepare total extracts of other chemovars of cannabis.

High Δ⁸-tetrahydrocannabinol (THC) cannabis chemovar, coarsely choppedin a cutter mill, is decarboxylated by heating at 145° C. for one hour.A quantity of 100 g of decarboxylated herb is packed into a cylindricalvessel fitted with a frit (mesh screen) to retain solid particles and atap in the exit tube. A second frit is placed over chopped cannabis toprevent splashing. The cannabis is moistened with 90% ethanol; a furtherquantity of ethanol is added to completely saturate the plant materialand allowed to stand for 24 hours. The tap is opened and the percolateis collected. A drip feed of ethanol is fixed up above the cannabis sothat the mass remains saturated with ethanol. Percolation is continued,reserving the percolate until the percolate is no longer darklycoloured, and when 1 ml of percolate tested by HPLC shows less than theequivalent of 0.1 mg of THC per ml. The presence of cannabinoid isrevealed by adding 0.1 ml of Fast Blue Test Solution is added to 1 mlpercolate. Cannabinoids produce characteristic colours (orange —CBD;pink—THC; and purple —CBD) in this test.

The reserved percolate is then evaporated to dryness in a rotaryevaporator and assayed by HPLC. Essential details of the assay methodare given below. A person skilled in the art will appreciate that otherconfigurations of column, mobile phase and operating conditions havingthe required discrimination and accuracy are suitable for the purposesof estimating cannabinoid content.

Extract: Typically 0.1 g of ground plant tissue/5 ml of chloroform,methanol 1.9 g Columns: S3 ODS2 3 × 0.46 cm pre-column and Discovery C815 × 0.46 cm analytical column Mobile Phase: 0.25% w/v acetic acid inWater: Methanol: Acetonitrile 6: 7: 16 (by volume) Flow Rate: 1 ml/minDetection: UV at 220 nm Injection volume: 2 μl

From Table 1 it can be seen that the extract so produced consists of THCprincipally, but there is also present some of the carboxylic acid(THCA), a little CBD, some CBDA and cannabinol. The remainder of theextract consists of ballast. Table 1 also gives the analysis of theextract produced from the high CBD chemovar using the method describedabove and shows that there are significant amounts of ballast present inthe dry extracts. The product is a dark oleoresin; the dark brown colourindicating that there is considerable oxidation of plant pigments. Themethod can be used to produce an extract from the high CBD chemovar bysubstitution of the appropriate plant mass.

Ethanol extraction may be optimised by varying pH and/or strength of theethanol solvent. Surprisingly it has been found that at high pH values,the carboxylic acids corresponding to cannabinoids are soluble in lowerconcentrations of ethanol/water, and that under these conditions thereis more complete extraction of total cannabinoid content as shown bygravimetric determination.

EXAMPLE 2 Extraction with Supercritical Carbon Dioxide

100 g of cannabis (high CBD chemovar) are coarsely chopped in a Hobartcutter mill then decarboxylated as described in Example 1. Plant mass ispacked, tamping down between successive layers, into the cavity of asupercritical fluid extraction apparatus. The mass is further compactedby axial pressure and frits are installed at either end of the cannabismass. Carbon dioxide at a pressure of 100 bar and a temperature of 32°C. is admitted to the apparatus and extraction continued for 4 hours. Atthe end of this time eluate is vented through a pressure reductionsystem and the extract emerging at atmospheric pressure is collected ina glass vessel as a yellow/brown oil.

The distillate is dissolved in dehydrated ethanol and cooled to atemperature of −20° C. ±1° C. for 24 hours and the waxy material removedby filtration. This process, known as “winterisation”, is used in theoil industry to de-wax oils, but only removes a percentage of lipidmaterial in extracts of cannabis (Table 1).

From Table 1 it can be seen that the product produced by this process isa yellow/brown oil which is lighter in colour than that produced byethanolic extraction but the extract still contains significantquantities of carotenoid pigments. It also contains significant amountsof cannabinol which is regarded by some authorities as a degradationproduct of THC and CBD.

EXAMPLE 3 Extraction with Heated Gas (Nitrogen)

Five kilos of coarsely chopped medicinal cannabis was loaded into thedrum of an apparatus of the type shown in FIG. 1. Distillation ofcannabinoids was effected with the use of pharmaceutical qualitynitrogen at a temperature between 175° C. and 250° C., which is belowthe temperature at which plant material chars or pyrolyses.

EXAMPLE 4 Extraction with Heated Gas (Reducing Steam)

Using apparatus of the type illustrated in FIG. 1, 5 kg of freshlyharvested cannabis was placed into the drum. The cannabis floweringheads and leaves were separated from stalk using a serrated comb withsharpened tines. The apparatus was equilibrated to a temperature of 110°C. and steam was introduced at 150° C. while the drum was set to rotate.A solution of sodium metabisulphite (10%) is introduced into the flow ofsteam in a quantity sufficient to give 10-500 parts of sulphur dioxideper million parts of wet biomass. When mixed with wet biomass, sodiummetabisulphite reacts to produce sulphur dioxide which provides anantioxidant environment in which the extraction can be carried out.Oxidation of the extract is thereby minimised.

Vapour leaving the chamber was condensed and produced a mixture of oiland aqueous layer. The volatile oil so produced is useful as a componentof medicinal flavouring and perfumery products. The collecting vesselwas fitted with two taps, one at the lowest point and the other at apoint on the wall of the glass container. After separation it ispossible to draw off the saturated aqueous layer which containsconsiderable amounts of terpenes and other odiferous principles; theoily cannabinoid-rich fraction is discharged through the upper tap. Bycontrolling the temperature of the condenser and the collection vesselit is possible to keep both aqueous and oily layers in non-viscous,liquid form for ease of handling.

It is apparent by observation of the oil level in the condenser whendistillation of this fraction is substantially complete. At this pointthe contents of the condenser are removed. Steam was replaced withnitrogen and the temperature raised to 218° C. The receptacle forcondensed liquor was replaced and the temperature in the reactorincreased to 218° C. The vapour now produced was condensed andcollected, as follows.

The vapour is admitted to a condenser which is cooled with water at atemperature of 50° C. Condensed material is still fluid at thistemperature and may be collected in a suitable receptacle.

Vapour leaving the condenser may be passed through a cold finger chilledwith carbon dioxide and acetone coolant which condenses valuablecomponents remaining in the vapour.

TABLE 1 Characteristics of Extract of Cannabis Method of Ballast (afterExtraction Chemovar Appearance of Extract THC THCA CBD CBDA CBNWinterisation 90% ethanol G1 Dark brown 50 4 1 2 2 40 (Example 1 90%ethanol G5 Dark green/brown 3 0.5 55 5 2 34 (Example 1) SCCO₂ G1Yellow/green/brown 60 6 1.5 2.5 2 ( ) (Example 2) oleoresin SCCO₂ G5Yellow/Green/brown 4 0.5 54 4 2 ( ) (Example 2) Distilled G1 LightYellow 98 trace 2.5 trace 0.5 trace (Example 4) Distilled G5 Lightyellow solid 1.5 trace 98 trace 0.5 trace (Example 4) G1 = “high THC”Chemovar G5 = “high CBD” Chemovar

EXAMPLE 5 Heated as Extraction from High CBD Cannabis Chemovar

The following studies were carried out using a pilot-scale version ofthe apparatus of FIG. 1. The apparatus can be run continuously andaccepts a charge of 50 g botanical raw material, which is heated forapproximately 15 mins.

The starting botanical raw material was a high CBD cannabis chemovar(designated G5) containing more than 90% of total cannabinoid as CBD andits precursors. Extraction was carried out by contacting the botanicalraw material with forced hot air flow at various selected temperatures.An inert atmosphere of nitrogen could be substituted for the flow ofair, for example if it is necessary to prevent oxidation of the minorcannabinoid component THC to CBN. Volatilised components were condensedby means of a “cold finger” filled with a salt/ice freezing mixture.

A series of experiments were carried out to determine the temperatureprofile required to resolve the cannabinoids, consisting predominantlyof CBD, from the unwanted terpene fraction (volatile oil fraction withgas chromatogram R.T.'s in the region 14 min-21 min). A basic approachof a lower temperature initial phase, to volatilise terpenes and otheressential oil components, followed by a higher temperature phase tovolatilise the higher boiling point cannabinoids was adopted. FIGS. 6-8,which show gas chromatography analysis of the condensed factionscollected following volatilisation at each of the chosen temperatures,plus GC analysis of starting material and spent herb. GC resultsobtained for the starting material (botanical raw material) and spentherb after each run are based on the analysis of total solventextractable fraction. This is representative of the qualitativecomposition of the herbal material before and after hot gas extraction.

The results obtained may be summarised as follows:

125° C./200° C. (FIG. 6.)

The low temperature phase produces no significant volatilisation of anycomponents (during the time period of this study). The highertemperature phase produces significant volatilisation of cannabinoidwhich is collected on the cold trap, but the volatile terpene fractionis not condensed and is lost from the system.

150° C./200° C. (FIG. 7.)

The low temperature phase produces significant volatilisation of bothterpene fraction and cannabinoid, both of which are collected on thecold trap to produce a complex mixed fraction. The most abundant peak inthe terpene region of the GC trace is a new compound not present in thestarting material, which may represent an oxidised terpene product. Thehigh temperature phase results in a cannabinoid-rich fraction containinglittle terpene.

175° C./200° C. (FIG. 8.)

The low temperature phase produces cannabinoid enriched rich fractionessentially free of terpenes. The high temperature phase produces afraction of comparable composition to that obtained during the lowtemperature phase.

The employment of a two-stage temperature profile can thus result insuccessful separation of cannabinoid from the terpene fraction,resulting in a cannabinoid enriched extract. Furthermore, it can bederived from these results that a single-stage temperature profile at atemperature of 175° C.-200° C. will also result in the production of acannabinoid-enriched fraction substantially free of terpenes (see FIG.6. 200° C. step, and FIG. 8).

Decarboxylation during the vaporisation process appeared to beessentially quantitative, with only neutral cannabinoid and no aciddetected in the condensed fractions. Both CBD principal cannabinoid andthe THC minor cannabinoid were present in the volatilised extract inapproximately the same ratio as detected in the herbal startingmaterial, indicating that no fractionation of cannabinoids had occurred.

Comparison of the results shown in FIGS. 6 and 7 indicates that atemperature of above 125° C. but below 150° C. is required topreferentially volatilise terpenes in this system. Optimisation of theextraction temperature within this range may allow preferentialvolatilisation of a terpene fraction which can be condensed andcollected fraction, substantially free of cannabinoids.

EXAMPLE 6 Heated Gas Extraction from High THC Cannabis Chemovar

The following studies were carried out using a pilot-scale version ofthe apparatus of FIG. 1. The apparatus can be run continuously andaccepts a charge of 50 g botanical raw material, which is heated forapproximately 15 mins.

The starting botanical raw material was a high THC cannabis chemovar(designated G1) containing more than 95% of total cannabinoid as THC andits precursors. Extraction was carried out by contacting the botanicalraw material with forced hot air flow at various selected temperatures.An inert atmosphere of nitrogen could be substituted for the flow ofair, for example to prevent oxidation of the cannabinoid component THCto CBN. Volatilised components were condensed by means of a “coldfinger” filled with a salt/ice freezing mixture.

A series of experiments were carried out to determine the temperatureprofile required to resolve the cannabinoids, consisting predominantlyof THC, from the unwanted terpene fraction (volatile oil fraction withgas chromatogram R.T.'s in the region 14 min-21 min). Specialconsiderations in the extraction of THC are to prevent/minimisethermo-oxidative degradation of THC to CBN and to prevent/minimisethermal isomerisation of Δ⁹-THC to Δ⁸-THC, whilst avoiding collection ofterpenes with the cannabinoid fraction.

A basic approach of a lower temperature initial phase, to volatiliseterpenes and other essential oil components, followed by a highertemperature phase to volatilise the higher boiling point cannabinoids,optionally with the inclusion of a third intermediate temperature phase,was adopted. FIGS. 9 and 10 show gas chromatography analysis of thecondensed factions collected following volatilisation at each of thechosen temperatures, plus GC analysis of starting material and spentherb.

GC results obtained for the starting material (botanical raw material)and spent herb after each run are based on the analysis of total solventextractable fraction. This is representative of the qualitativecomposition of the herbal material before and after hot gas extraction.

The results obtained are summarised in the following table:

TABLE 2 SAMPLE Δ⁹-THC CBN Δ⁸-THC CBD THC:CBN BRM (G1) 75.5%  3.0%  0.3%1.9%   28:1 Run 1 125° C. 51.5%  6.2%  0.4% 1.2%  8.3:1 200° C. 63.3%12.8%  0.5% 1.1%  4.9:1 spent herb  3.0% 11.1% 17.2% N.D.  0.3:1 Run 2 90° C. 58.0%  5.6%  0.3% 1.8% 10.4:1 150° C. 82.7%  9.6%  0.4% 1.5% 8.6:1 200° C. 77.1% 14.1%  0.7% 1.0%  5.5:1 spent herb 54.0% 25.7% 2.6% N.D.  2.1:1 Run 3  60° C. 78.6%  7.2% N.D. N.D. 10.9:1 125° C.75.3%  6.0% N.D. 1.8% 12.6:1 200° C. 83.0% 10.2%  0.2% 1.6%  8.1:1 spentherb 64.1% 23.7%  0.6% 0.9%  2.7:1 The THC:CBN ratio is an indicator ofthe thermo-oxidative stress to which the material has been subjectduring the vaporisation process.

The results from run 3 indicate that a temperature of above 60° C. isrequired in order to volatilise terpenes. At a temperature of 90° C.(run 2) terpenes are volatilised, but only the less volatile terpenesare condensed. These results suggest that a temperature between 60° C.and 90° C. may be optimum for volatilisation and condensation of aseparate terpene fraction.

The results from run 2 indicate that at 150° C. a cannabinoid-richfraction is condensed, which is substantially free of terpenes. Asimilar profile is obtained at 200° C., however at this temperature theamount of Δ⁸-THC and CBN is increased, indicating thermal-oxidativedegradation and thermal isomerisation of Δ⁹-THC. Similar results areseen in run 3, where the fraction obtained at 200° C. is free ofterpenes but contains a higher proportion of Δ⁸-THC and CBN. It istherefore preferred to use a temperature which is as low as possible inorder to minimise thermal-oxidative degradation and thermalisomerisation of Δ⁹-THC, whilst still resulting in a fraction which issubstantially free of terpenes. A range of from 130° C. to 175° C. ispreferred.

EXAMPLE 7 Purification of an Ethanol Extract by Extraction with HeatedGas

High pH and low pH ethanolic solutions were prepared by adding 5 ml ofm/1 sodium hydroxide or hydrochloric acid solution to absolute ethanoland sufficient purified water to produce 100 ml of solvent. Thisquantity of solvent was used to percolate 10 g of cannabis herb, asdescribed in Example 1.

Percolation of the cannabis herb was continued to exhaustion asdescribed in Example 1 and evaporated to a soft extract (as defined inthe British Pharmacopoeia). The extract was re-dissolved in ethanol togive a solution with a viscosity in the range 100-500,000 cps(preferably 50-150,000 cps using a Brookfield viscometer) and pouredonto the cylindrical column of an apparatus of the type illustrated inFIG. 5. The column was constructed of borosilicate glass and packed withglass wool. Sufficient quantity of extract was added to coat but notsaturate the column. Care was taken to ensure that the extract wasretained within the pre-packed column.

The loaded column was assembled and connected to a condenser assemblyand an electrical heater/blower. Air at a temperature of 60° C.-120° C.was blown through the cylinder and maintained at the same temperature.At this temperature volatile components consisting mainly of water,alcohols, and low boiling point terpenes are volatilised then condensedand collected in the receiver. When distillation of these low boilingcomponents was substantially complete (indicated by a rise intemperature in the vapour leaving the column), the supply of gas wasstopped and the receiver changed or emptied.

The temperature of the cylindrical column was increased to 218° C. andgas blown through the cylinder for 20 minutes. The gas was re-circulatedthrough the cylinder with valve 76 closed and valve 73 opened. Duringthis period cannabinoid acids are decarboxylated. Decarboxylation issubstantially complete when a sample is taken from sampling port 74shows that the free cannabinoid has reached a maximum level, measured byHPLC. At this point valve 76 was opened and valve 73 closed. Vapour wascondensed in the condenser assembly and the condensed distillatecollected. The distillate so produced consists of the total cannabinoidsof the extract with very little cannabinoid acid, and is suitable forformulation into pharmaceutical dosage forms.

EXAMPLE 8 Preparation of a Methanolic Extract

Total extracts of high THC and high CBD cannabis chemovars were preparedusing ethanol as follows:

Biomass from each chemovar was separately extracted in a column withmethanol at room temperature, and the pooled percolate was collected.Solvent was removed by evaporation in a rotary evaporator at atemperature not exceeding 43° C.

1. A process for selectively preparing a cannabinoid-containing extractfrom cannabis plant material or a solvent extract thereof loaded onto aninert matrix material, comprising: contacting the cannabis plantmaterial or solvent extract with a heated gas at a temperature which isgreater than 100° C. and sufficient to volatilise at least onecannabinoid but does not cause pyrolysis of the cannabis plant materialor solvent extract thereby volatilising the at least one cannabinoid toform a vapour, wherein the heated gas is one of a reducing gas and anon-oxidising gas; wherein the temperature to which the gas is heated isa temperature at which the target cannabinoid will volatilise condensingthe vapour; and collecting the condensed vapour to form a selectivecannabinoid-containing extract.
 2. A process according to claim 1wherein the cannabinoid-containing extract is substantially free ofballast.
 3. A process according to claim 2 wherein thecannabinoid-containing extract is substantially free of fats, waxes,carbohydrates, proteins and sugars.
 4. A process according to claim 1wherein the cannabinoid-containing extract is substantially free ofterpenes.
 5. A process according to claim 1 wherein thecannabinoid-containing extract is substantially free from waxes, sterolsand other lipid soluble components of solvent extracts.
 6. A processaccording to claim 1 wherein the cannabinoid-containing extract containsTHC.
 7. A process according to claim 1 wherein thecannabinoid-containing extract contains CBD.
 8. A process according toclaim 1 wherein the heated gas is forced upwardly through the cannabisplant material, which is retained in a perforated container, or thesolvent extract.
 9. A process according to claim 1 wherein the heatedgas is blown onto the cannabis plant material or solvent extract.
 10. Aprocess according to claim 1 wherein the cannabis plant material orsolvent extract is subjected to continuous agitation.
 11. A processaccording to claim 10 wherein the continuous agitation is effected bysubjecting the cannabis plant material or solvent extract to a rotaryaction.
 12. A process according to claim 1 wherein the cannabis plantmaterial or solvent extract is presented to the heated gas in acounter-current manner.
 13. A process according to claim 1 wherein thecannabis plant material is wet plant material and the process furthercomprises a pre-treatment step in which the cannabis plant material iscontacted with a heated gas at a temperature which is sufficient to drythe cannabis plant material.
 14. A process according to claim 1 whereinthe reducing gas is one of nitrogen, carbon dioxide, helium and argon.15. A process according to claim 1 wherein the non-oxidising gas is drysteam.
 16. A process according to claim 1 wherein the reducing gas issteam to which has been added sodium metabisulphite in a quantitysufficient to produce 10-500 parts of sulphur dioxide per million partsof the cannabis plant material or solvent extract.
 17. A processaccording to claim 1 wherein the vapour is treated to remove particulatematter prior to the condensing step.
 18. A process according to claim 1wherein the temperature of the heated gas used to volatilise thecannabinoids is selected to effect decarboxylation of cannabinoid acidspresent to free cannabinoids and to volatilise the free cannabinoids.19. A process according to claim 18 wherein the temperature of theheated gas used to volatilise the cannabinoids is in the range of from105° C. to 450° C.
 20. A process according to claim 19 wherein thetemperature of the heated gas used to volatilise the cannabinoids is inthe range of from 105° C. to 225° C.
 21. A process according to claim 20wherein the cannabis plant material or solvent extract is a high CBDcannabis plant or a solvent extract thereof and the temperature of theheated gas used to volatilise the cannabinoids is in the range of from120° C. to 140° C.
 22. A process according to claim 20 wherein thecannabis plant material or solvent extract is a high THC cannabis plantor a solvent extract thereof and the temperature of the heated gas usedto volatilise the cannabinoids is in the range of from 105° C. to 120°C.
 23. A process according to claim 1 wherein the temperature of theheated gas used to volatilise the at least one cannabinoid of thenatural product is varied in at least two discrete steps.
 24. A processaccording to claim 23 wherein the step of contacting comprisescontacting the cannabis plant material or solvent extract with a heatedgas at a first temperature and contacting the cannabis plant material orsolvent extract with a heated gas at a second temperature which isgreater than the first temperature, the second temperature being greaterthan 100° C. and sufficient to volatilise the at least one or morecannabinoids but does not cause pyrolysis of the cannabis plant materialor solvent extract, and wherein the condensing step condenses vapourformed at least one of the first and second temperatures.
 25. A processaccording to claim 24 wherein vapours formed at the first and the secondtemperatures are condensed and collected in separate fractions.
 26. Aprocess according to claim 24 wherein the cannabis plant material orsolvent extract is a high CBD cannabis plant or solvent extract thereof,the first temperature is in the range of from 125° C. to 150° C., andthe second temperature is in the range of from 175° C. to 200° C.
 27. Aprocess according to claim 24 wherein the cannabis plant material orsolvent extract is a high THC cannabis plant or extract thereof, thefirst temperature is in the range of from 60° C. to 90° C., and thesecond temperature is in the range of from 130° C. to 175° C.
 28. Acannabinoid-containing extract which is substantially free of volatileterpenes, comprising: about 98% tetrahydrocannabinol (THC); about 2.5%cannabidiol (CBD); about 0.5% cannabinol (CBN); and only trace amountsof tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) andballast.